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Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

Schreiner, Jens and Thommen, Daniela Stefanie and Herzig, Petra and Bacac, Marina and Klein, Christian G. and Roller, Andreas and Belousov, Anton and Levitsky, Victor and Savic, Spasenija and Moersig, Wolfgang and Uhlenbrock, Franziska and Heinzelmann-Schwarz, Viola A. and Umana, Pablo and Pisa, Pavel and von Bergwelt-Baildon, M. and Lardinois, Didier and Müller, Philipp and Karanikas, Vaios and Zippelius, Alfred. (2016) Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor. Oncoimmunology, 5 (2). : e1062969.

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Official URL: http://edoc.unibas.ch/43261/

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Abstract

T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Onkologie > Translationale Onkologie (Zippelius)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Onkologie > Translationale Onkologie (Zippelius)
UniBasel Contributors:Thommen, Daniela
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Taylor & Francis
ISSN:2162-4011
e-ISSN:2162-402X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Dec 2016 09:39
Deposited On:06 Dec 2016 09:39

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